Use of selegiline for the treatment of epileptic disorders

ABSTRACT

The invention relates to the use of selegiline (=L-N-(1-phenylisopropyl)-N-methyl-N-propynylamine) or pharmaceutically utilizable salts thereof in pharmaceuticals with an antiepileptic effect.

This application is a 371 of PCT/DE95/00981 filed Jul. 27, 1995.

The invention relates to the use of selegiline(=L-N-(1-phenylisopropyl)-N-methyl-N-propynylamine) or itspharmaceutically utilizable salts in pharmaceuticals with anantiepileptic effect.

It is known that selegiline is a blocker of monoamine oxidase type B.This enzyme breaks down monoaminergic neurotransmitters (especiallydopamine) in gliacytes, which leads to termination of the effect ofdopamine. Blockade of the enzyme results in an increase in the dopaminelevel in the brain. Because of this effect, selegiline is used asadjunct treatment together with levodopa in the therapy of Parkinson'sdisease (marketed under the proprietary name Deprenyl for example).

Further effects of N-(1-phenylisopropyl)-N-methyl-N-propynylamine and ofthe L form (selegiline) are described in the literature.

WO 92/17 169 A1 describes a neuroprotective effect with an as yetundefined mechanism of action. It is therefore proposed for use asneuroprotective agent (prevention of nerve cell loss in disorders of theCNS, in particular Parkinson's disease, cerebral trauma and spinal cordtrauma).

Furthermore the following effects of selegiline, with or withoutcombination partners, are patented, but no clear mechanisms of actionare known for these:

Therapy of

a) immune system dysfunctions;

b) Cushing's syndrome;

c) psychological withdrawal symptoms after cocaine, alcohol and opiateaddiction;

d) manifestations of ageing;

e) Alzheimer's disease;

f) psychological symptoms associated with tobacco withdrawal;

g) schizophrenia;

h) psychological symptoms associated with pre-menstrual syndrome;

i) travel sickness (kinetosis);

j) high blood pressure;

k) depression in combination with other products (U.S. Pat. No.5,192,808, U.S. Pat. No. 4,861,800, U.S. Pat. No. 4,868,218, U.S. Pat.No. 4,579,870, CA 1 322 530, WO 92/21333 A1, WO 91/18592 A1, WO90/04387, WO 90/01928, WO 88/04552, EP 252 290 A1)

A further use for which a patent has been applied for is as marker forglioses in degenerative disorders using labelled selegiline as marker ofgliacytes (U.S. Pat. No. 7,052,921, U.S. Pat. No. 6,853,119). In thisindication there is also mention of the diagnosis of gliotic centresbefore surgical removal of these scars from the brain of epilepsypatients. However, this is exclusively a diagnostic use. The authorsstate that there are no indications whatsoever of a pathogeneticinvolvement of monoamine oxidase B in epilepsy, selegiline is suitableonly as marker for gliacytes (Kumlien E. et al., Epilepsia, Vol. 33, No.4. 1992, 610 ff).

There are a number of anticonvulsants on the market for the treatment ofepilepsies. Phenytoin and carbamezepine may be mentioned as theprincipal representatives. The anticonvulsants used to date for therapylead to suppression of the convulsion but have no effect on thedevelopment of the actual epileptic focus.

It is an object of the present invention to provide pharmaceuticals withgood anticonvulsant and antiepileptogenic effects.

It has been found, surprisingly, that selegiline shows a potentanticonvulsant and antiepileptogenic effect. The threshold for theinduction of focal and generalized convulsions was raised to a similarextent as by the standard anticonvulsants carbamazepine and phenytoin.The convulsion threshold is regarded as the most importantcharacteristic of an anticonvulsant effect. Epilepsy is a thresholdphenomenon, and a convulsion is induced in humans by the threshold beingexceeded by endogeneous or exogenous stimuli. Drugs of first choice forthe treatment of epilepsy raise the threshold, while drugs of secondchoice often do not influence the threshold but only reduce the severityof the convulsions in the individual episode. An effect of selegiline onthe threshold has also been demonstrated in a classical model ofepilepsy, the maximum electric shock.

On the basis of the pharmacological investigations, selegiline shows aneffect similar to that of drugs of first choice.

In epilepsy patients there is often a progression of the disorder withtime, the attacks become more severe and the patient responds less wellto the treatment.

It is therefore of particular interest that selegiline is also able toslow down the development of epileptic focus and thus halt progressionof the disorder.

The antiepileptic effect ofN-(1-phenylisopropyl)-N-methyl-N-propynylamine is strictlystereospecific. Only the L form (selegiline) has an antiepilepticeffect. The D form is inactive. At doses at which the L form has no sideeffects, it induces severe amphetamine-like side effects.

PHARMACOLOGICAL INVESTIGATIONS

The investigation of selegiline in amygdala kindling as model of focalepilepsy and as model of epileptogenesis started from the findings onthe neuroprotective effect of selegiline.

In amygdala kindling there is induction of an epileptic focus byrepeated very weak stimulation of one region of the rat brain throughdeep electrodes. This focus is permanent, and animals which arecompletely kindled are to be termed epileptic. It is then possible toinvestigate anticonvulsants in this model. When they are given tocompletely kindled animals and a convulsion is induced, the thresholdfor induction of the convulsion may be raised (greater stimulation isnecessary to induce a convulsion), and the convulsion which isnevertheless induced may be weaker.

However, it is also possible to investigate in this model drugswhich--irrespective of their effect on the induced convulsion--suppressdevelopment of the epileptic focus. The anticonvulsant effect isindependent of the effect on the development of the epileptic focus.

Data on the anticonvulsant effect

Method of Freeman F G et al., Brain Res. Bull 1981; 7; 629-633, modifiedby Rundfeldt C et al., Neuropharmacology 1990; 29; 845-851.

Amygdala kindling, raising of the threshold for induction of focalconvulsions in completely kindled rats:

    ______________________________________                   % rise in                   convulsion                   threshold    ______________________________________    L form (selegiline)     5 mg/kg i. p.    0    10 mg/kg i. p.   +130-+250    20 mg/kg i. p.   +70    40 mg/kg i. p.   +41    D form    10 mg/kg         -12    ______________________________________

Effect on the development of the epileptic focus in kindling

Method of Racine R et al., Electroencephalograph Clin Neurophysiol.1975; 38; 355-365, see also Silver J M et al., Ann Neurol 1991; 29;356-363.

When the epileptic focus is produced in the kindling there are plasticchanges in the brain. Epileptic discharges with a particular totalduration are necessary for complete expression of the epileptic focus.During treatment with selegiline (5 and 10 mg/kg, 1×/day) 35% and 53%more stimulations are needed until the first generalized convulsionoccurs. In addition, significantly longer epileptic discharges arenecessary to establish the focus (52% and 117%). This indicates thatselegiline slows down the plastic changes in the brain necessary toestablish the focus.

After discontinuation of the treatment, the duration of the epilepticdischarges which can be induced in completely kindled animals issignificantly shorter than in control animals.

This shows that the epileptic focus is less strongly expressed than inthe control group.

Selegiline can thus be used as highly specific and effective medicinalsubstance for the treatment of epileptic disorders. There is, moreover,not only suppression of the convulsion but also slowing down of theprogression of the disorder.

The compound according to the invention and processes for itspreparation are known.

The compounds can be converted in a known manner into the usualformulations such as tablets, capsules, coated tablets, pills, granules,syrups, emulsions, suspensions and solutions using inert, non-toxic,pharmaceutically suitable excipients or solvents.

In these cases the daily dose of selegiline on oral or parenteraladministration should be 5-20 mg.

It is possible if necessary to deviate from the stated amounts, inparticular depending on the body weight and the specific mode ofadministration.

What is claimed is:
 1. A method for the treatment of epilepsy in apatient comprising administering to said patient an effective amount ofdeprenyl or salts of deprenyl to suppress the development of epilepticfoci.
 2. A method for slowing progression of an epileptic disorder in apatient comprising administering to said patient an effective amount ofdeprenyl or salts of deprenyl to slow the development of an epilepticfocus.
 3. A method for curing an epileptic disorder in a patientcomprising administering to said patient an effective amount of deprenylor salts of deprenyl to suppress the development of epileptic foci.
 4. Amethod for preventing an epileptic disorder in a patient comprisingadministering to said patient an effective amount of deprenyl or saltsof deprenyl to suppress the development of epileptic foci.